Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/81—Amides; Imides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
  • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
  • C07C243/38—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to carbon atoms of six-membered aromatic rings
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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
  • C07C51/58—Preparation of carboxylic acid halides
  • C07C51/60—Preparation of carboxylic acid halides by conversion of carboxylic acids or their anhydrides or esters, lactones, salts into halides with the same carboxylic acid part
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/81—Amides; Imides
  • C07D213/82—Amides; Imides in position 3
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
  • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
  • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
  • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
  • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D307/14—Radicals substituted by nitrogen atoms not forming part of a nitro radical
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
  • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
  • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
  • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
  • C07D317/58—Radicals substituted by nitrogen atoms
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• This application relates to novel hydrazine compounds useful as cytostatic agents and, particularly, inhibit the growth of transplantable tumors in both mice and rats. Thus, they are active, for example, against Walker tumors, Erlich carcinoma and Erlich ascites carcinoma.
• novel compounds in this invention are selected from the group consisting of compounds of the and pharmaceutically acceptable acid addition salts thereof, wherein X is a phenyl radical bearing substituents selected from the group consisting of amino, acylamino, ureido, (alkylsulfonyl) -amino, guanidino, amidino, aminoalkyl, carbamoyl, allophanoyl, sulfamoyl, alkylsulfonyl, nitro, (2-methylhydrazino)-methyl, acyl, phenyl, alkyl, trifluoromethyl, halogen, hydroxy, alkoxy, alkanoyloxy, mercapto and alkylthio; at least one substituent being selected from the group consisting of amino, acylamino, .ureido, (alkylsulfonyl)-amino, guanidino, amidino, aminoalkyl, carbamo
• Primary, secondary and tertiary amino groups such as amino, lower alkylamino, for example, methylamino, and di-lower alkylamino, for example, dimethylamino, diethylamino;
• Acylamino groups wherein the acylating moiety can be formed from aliphatic, aromatic or heterocyclic acids and the amino group of which can be primary or secondary such as lower alkanoylamino groups, for example, N-acetyl N methylamino, acetylamino and pivaloylamino; acylamino groups wherein the acyl moiety is the residue of a naturally occurring a-amino acid, for example, alkanoylamino; other aliphatic acylamino groups, for example, succinimido; aroylamino groups, for example, benzoylamino and phthalimido; heterocyclic acyl- 3,534,100 Patented Oct. 13, 1970 ice.
• hetero moiety is a one to two hetero atom nitrogen and/or oxygen containing 5 to 6 membered heterocyclic ring as well as heterocyclic acylamino groups wherein the heterocyclic ring bears further substituents such as lower alkyl, for example, nicotinoylamino, isonicotinoylamino, (methylisoxagolylcarbonyl)- amino and (methyloxazolylcarbonyl)-am1no;
• Ureido groups the hydrogen atoms of which can be in part or completely replaced by saturated or unsaturated aliphatic, cycloaliphatic, araliphatic, aromatic or heterocyclic radicals which themselves can bear further functional groups, for example, methylureido, isopropylureido;
• Alkylsulfonyl-amino groups for example, (methylsulfonylamino) Guanidino groups, the hydrogen atoms of which can be in part or completely replaced by saturated or unsaturated aliphatic, cycloaliphatic, araliphatic, aromatic or heterocyclic radicals which themselves can bear further functional groups, for example, methyl guanidino, isopropylguanidino, (hydroxyethyl)-guanidino;
• Amidino groups the hydrogen atoms of which can be in part or completely replaced by saturated or unsaturated aliphatic, cycloaliphatic, araliphatic, aromatic or hetero cyclic radicals which themselves can bear further functional groups, for example, methylamidino, diisopro ylamidino, cyclopropylamidino, phenylamidino, benzylamidino, isoxazolylamidino and (hydroxyethyl)-amidino;
• Primary, secondary and tertiary amino-lower alkyl groups for example, aminomethyl, aminoethyl, aminopropyl, methylaminomethyl, ethylaminoethyl, methylaminopropyl, dimethylaminomethyl, diethylaminoethyl and dimethylaminopropyl;
• Carbamoyl groups the hydrogen atoms of which can be replaced by saturated or unsaturated aliphatic or alicyclic radicals which themselves can bear further functional groups or aromatic or heterocyclic radicals, for example, mono and dialkylcarbamoyl such as N-methyl-carbamoyl, N,N dimethylcarbamoyl, N isopropylcarbamoyl, N-isobutylcarbamoyl, N-tert.-butylcarbamoyl, N,N-diisopropylcarbamoyl, N-tert.-amylcarbamoyl, N-tert.-octylcarbamoyl; as well as N-alkoxyalkylcarbamoyl groups such as methoxyethylcarbamoyl; N-hydroxyalkylcarbamoyl, such as hydroxyethylcarbamoyl; N-alkylthioal
• Allophanoyl groups the hydrogen atoms of which can be in part or completely replaced by saturated or unsaturated aliphatic, cycloaliphatic, araliphatic, aromatic or heterocyclic radicals which themselves can bear further functional groups, for example, 4-methylallophanoyl, 2- isopropylallophanoyl;
• Sulfamoyl groups the hydrogen atoms of which can be substituted by alkyl groups such as lower alkyl groups, for example, N,N-dimethylsulfamoyl;
• Phenyl radicals either unsubstituted or bearing one of the above-named substituents, for example, (Z-methylhydrazinomethyl)-phenyl, carbamoylphenyl and acylaminophenyl such as [(5-methyl-3-isoxazolylcarbonyl)- aminoJ-phenyl and ureidophenyl;
• Lower alkyl groups for example, methyl, ethyl and isopropyl
• R is selected from the group consisting of nitro, amidino, guanidino, benzoyl, amino, lower alkylamino, and di-lower alkylamino:
• Z is selected from the group consisting of carbonyl and sulfonyl
• R is selected from the group con- ([JHaNHNHCHa wherein Z is selected from the group consisting of carbonyl and sulfonyl
• R is selected from the group consisting of lower alkyl, the residue of a naturally occurring ot-amino acid devoid of its carboxyl group, phenyl amino, lower alkylamino, di-lower alkylamino, hydroxylower alkylamino, a to 6 membered heterocyclic ring containing one to two hetero atoms selected from the group consisting of nitrogen and oxygen, and a said heterocyclic ring bearing a lower alkyl substituent.
• the compounds of Formula I can be prepared by aralkylation of a compound of the formula wherein the hydrogen atoms of the hydrazine group may partially be substituted by protecting groups such as acyl, carbalkoxy, carbobenzoxy of benxyl,
• the hydrogen atoms of the hydrazine group may partially be substituted by protecting groups such as acyl, carbalkoxy, carbobenzoxy or benzyl;
• One embodiment of the invention consists of aralkylating methylhydrazine or a methylhydrazine, the nitrogen atoms of which are partially substituted by protecting groups, with an agent yielding the residue X'CH
• This aralkylation can be effected, for example, by use of the following aralkylating agents: 4-carbamoylbenzyl bromide, 4-cyanobenzyl bromide, 4-carbalkoxybenzyl bromide, 2-cyanobenzyl bromide, 4-nitrobenzyl bromide, 3- nitrobenzyl bromide, 4-carbamoyl-2-chlorobenzyl bromide, 4-acylaminobenzyl bromide, 1,2-bis-(bromomethyl)-benzene, 4,4'-bis-(chloromethyl)-biphenyl, 4-benzoylbenzyl bromide, 4-acetylbenzyl bromide, and the like.
• a dihalo compound as
• reaction product can be purified by conventional methods, for example, via extraction, crystallization or distillation.
• the introduction of the aralkyl moiety can also be effected by a reaction of methylhydrazine or methylhydrazine partially substituted by protecting groups, for example, l-methyl-l-acetyl-hydrazine with a carbonyl compound, followed by reduction of the so-formed hydrazone, as well as eventual splitting off of the protecting groups.
• This reaction can suitably be effected via a short heating of the reaction components in a solvent, such as, for example, alcohol, and reduction of the resulting hydrazone in the presence of a hydrogenation catalyst, such as palladium or platinum.
• hydrazine compounds of Formula VIII are methylated.
• This methylation can be conducted, for example, with the help of a methylating agent, such as, methyliodide or dimethylsulphate, under the conditions previously described for the aralkylation reaction.
• a methylating agent such as, methyliodide or dimethylsulphate
• the introduction of the methyl group can also be effected via reaction of a compound of Formula VIII above with formaldehyde, followed by reduction of the condensation product. Condensation is suitably eifected with equimolar amounts of the hydrazine of Formula VIII and of the formaldehyde.
• the hydrogenation of the condensation product can proceed simultaneously with the condensation reaction or subsequent thereto.
• it is conducted in the presence of a hydrogenation catalyst, such as platinum or palladium, until the absorption of an equimolar amount of hydrogen.
• the working up of the reaction mixture can be effected by conventional means, for example, via fractional distillation.
• Products of Formula I above can also be obtained via methylation of a product obtained via aralkylation of a compound of Formulae IX or X above.
• reaction products formed by the above outlined processes can, if desired, be additionally substituted in the phenyl ring.
• compounds of Formula 1 above the hydrazine group of which is provided with protecting groups such as those previously described, can be nitrated, for example, via treatment with potassium nitrate in concentrated sulfuric acid at a temperature of from about C. to about 70 C.
• a suitable catalyst for example, ferric chloride, at slightly elevated temperatures, halogen atoms can be introduced as substituents on the benzene nucleus.
• the conversion of the moiety X into the moiety X can be effected in the above described reaction procedures at any point of time.
• the acid is converted into a reactive derivative, for example, into an acid chloride or a mixed anhydride, for example, with a carbonic acid monoester or into an activated ester, for example, a cyanomethylester.
• the acid can also be amidated directly via use of a condensation agent such as dicyclohexylcarbodiimide.
• a condensation agent such as dicyclohexylcarbodiimide.
• the above-mentioned amides can also be obtained in the presence of a strong acid from [(2-methyl-l,Z-dicarbobenzoxyhydrazino)-methyl]-benzonitrile via reaction with olefins, for example, isobutylene or secondary or tertiary alcohols.
• Hydrolysis of the nitriles by means of strong acids or with hydrigen peroxide and alkalis produces N-unsubstituted benzamides.
• Protecting groups are subsequently removed from carbamoyl compounds obtained according to this method via hydrogenolysis or treatment with a hydrogen bromide/ glacial acetic acid solution.
• the resulting hydrobromides obtained by the latter method can, if desired, be converted into corresponding free bases and/ or into other salts.
• acylamino substituted compounds of the invention are preferably prepared via acylation of, for example, 1-methyl-1,2-dicarbobenzoxy-Z-(p-aminobenzyl)-hydrazine, which itself, for example, can be obtained via reduction of the corresponding nitro or azo compound.
• the acylation can be effected, for example, by use of a reactive derivative of the desired carboxylic acid or sulfonic acid, or from the free acid by use of a condensation agent such as dicyclohexylcarbodiimide.
• the subsequent removal of the protecting groups can be effected in ways known per se; for example, via hydrogenolysis or hydrolysis with hydrogen bromide in glacial acetic acid.
• Accessible from the same intermediate amino compounds are ureido compounds via treatment with cyanates or isocyanates, as well as guanidines by treatment with cyanamide and its derivatives (for example, methylisothiourea sulphate).
• Amidino or substituted amidino compounds of Formula I are advantageously prepared from methylhydrazinomethyl-benzonitriles, the hydrazine group of which is substituted by protecting groups, via the corresponding imido ether, which can be obtained via reaction of the nitrile with alcohol and mineral acid.
• the imido ether By reaction of the imido ether with ammonia or a primary or secondary amine, the desired amidino compound is obtained.
• Suitably protected methylhydrazinomethyl-benzonitriles can also be reacted directly with salts of amines, for example, isopropylamine hydrochloride or isopropylamine tosylate at elevated temperatures, and the desired products of Formula I can be obtained via subsequent removal of the protecting groups.
• One further method consists of converting a mono-substituted methyl hydrazinomethyl-benzamide, the hydrazine groups of which is substituted by protecting groups, for example, 4-[ (Z-methyl 1,2 dicarbobenzoxy-hydrazino)- methylJ-benzoic acid isopropylamide, via reaction with a phosphorus halide, for example, phosphorus pentachloride, into corresponding imido halides, which then, in turn, can be reacted with ammonia, primary, or secondary amines, whereby there is obtained upon removal of the protecting groups, amidines and monoor disubstituted amidines.
• protecting groups for example, 4-[ (Z-methyl 1,2 dicarbobenzoxy-hydrazino)- methylJ-benzoic acid isopropylamide
• the substituted aromatic hydrazine compounds of Formula I form pharmaceutically acceptable acid addition salts with both pharmaceutically acceptable inorganic and organic acids, such as, for example, hydrohalic acids, as hydrogen chloride, hydrogen bromide, hydrogen iodide, as well as other mineral acids, such as sulfuric acid, phosphoric acid, nitric acid, and with organic acids, such as tartaric acid, citric acid, oxalic acid, camphorsulfonic acid, ethanesulfonic acid, toluenesulfonic acid, salicylic acid, ascorbic acid, maleic acid, manclelic acid, and the like.
• Preferred salts are the hydrohalides, especially the hydrochloride.
• the acid addition salts can suitably be prepared via treatment of the hydrazine derivative in an inert solvent with the corresponding acid.
• the compounds of Formula I are active cytostatic agents, as described above. Also these compounds cause decomposition of macromolecular desoxyribonucleic acid in solution.
• the compounds can be administered internally in the form of conventional pharmaceutical preparations, for example, the bases of Formula I or their pharmaceutically acceptable acid addition salts can be administered in conventional enteral or parenteral pharmaceutical excipients containing organic and/or inorganic inert carriers, such as Water, gelatin, lactose, starch, magnesium stearate, talc, plant oils, gums, alcohol, Vaseline, or the like.
• the pharmaceutical preparations can be in conventional solid forms, for example, tablets, drages, suppositories, capsules, or the like, or conventional liquid forms, such as suspensions, emulsions, or the like. If desired, they can be sterilized and/ or contain conventional pharmaceutical adjuvants, such as, preservatives, stabilizing agents, wetting agents, emulsifying agents, buffers, or salts used for the adjustment of osmotic pressure.
• the pharmaceutical preparations can also contain other therapeutically active materials.
• Example 1 To a suspension of 4.8 g. of sodium hydride and 200 ml. of dimethylformamide there was added dropwise in the course of 30 minutes a solution of 45.4 g. of 1,4-bis- [(1,2-dicarbethoxy-hydrazino)-methyl] -benzene in ml. of dimethylformamide. The resulting mixture was stirred for a further 3 hours and then 30 g. of methyl iodide were added at one time to the turbid solution. The reaction mixture was then heated for 4 hours at 100". After cooling, the reaction mixture was distilled under reduced pressure, the residue taken up in 300 ml. of chloroform, the resulting solution twice shaken each time with 200 ml.
• the starting material used above was prepared as follows: 10.6 g. of p-xylene and 8.7 g. of azodicarboxylic acid ethyl ester were heated together under a nitrogen atmosphere at 140150 for 72 hours. During this time, there was thrice added to the reaction mixture, at intervals of 12 hours, three portions of 8.7 g. of azodicarboxylic acid ethyl ester.
• Example 2 A mixture of 26 g. of l-methyl-l,Z-diacetyl-hydrazine and 30 ml. of absolute ethanol was poured into a solution of 4.6 g. of sodium in 120 ml. of absolute ethyl alcohol maintained at and immediately thereafter g. of 1,2-bis-(bromo methyl)-benzene were added to the reaction mixture. 1
• Example 3 A mixture of 44 g. of l-methyl-l,2-diacetyl hydrazine and ml. of absolute ethanol was added to a solution of 7.7 g. of sodium in 200 ml. of absolute ethyl alcohol. 57 g. of 4-nitro-benzyl chloride in 60 ml. of dimethylformamide were then added dropwise thereto in the course of 30 minutes with stirring and heating. The reaction mixture was then heated for 1 hour, cooled to 0, the separated precipitate filtered OE and twice washed, each time with ml. of ethanol. The filtrate was then evaporated in vacuo and the residue partitioned between 200 ml. of water and 300 ml. of methylene chloride.
• the aqueous phase was separated, and again extracted, this time with 200 ml. of methylene chloride.
• the methylene chloride extracts were then washed with 200 ml. of 2 N sodium hydroxide and 200 ml. of water, dried over sodium sulfate and concentrated.
• the residue was recrystallized from chloroform/ ethanol yielding 1-methyl-2-(4- nitro benzyl) 1,2 diacetyl-hydrazine, which melted at 141142.
• Example 4 24.7 g. of 1-methyl-1,2-diacetyl-hydrazine were added to a solution of 4.38 g. of sodium in ml. of absolute ethanol and 27.5 g. of 2-cyano-benzyl chloride were then added to the resulting mixture, which was then heated under reflux for 4 hours. The precipitated salt was filtered oil and the filtrate concentrated in vacuo. The residue was treated with water and extracted over 15 hours with a mixture of ether and methylene chloride (2:1). Concentration of the extract yielded a residue that was heated under a nitrogen atmosphere for 2 hours with a mixture of 85 ml. of concentrated hydrochloric acid and 67 ml. of water.
• reaction solution was then concentrated and rendered alkaline by addition of sodium hydroxide, whereupon 2-[(Z-methyl-hydrazino)-methyl] benzamide separated out.
• the dihydrobromide prepared therefrom was crystallized from glacial acetic acid and melted at 240-242.
• Example 5 A solution of 25.4 g. of l-methyl-l,Z-dibenzoyl-hydrazine in 50 ml. of dimethylformamide was added dropwise, with stirring and cooling at 20-30", to a suspension of 2.4 g. of sodium hydride in 50 ml. of dimethylformamide. 17.2 g. of 3-nitro-benzyl chloride was then added to the reaction mixture, and the resulting mixture permitted to stand overnight at room temperature. The greater part of the dimethylformamide was then distilled off under reduced pressure, the residue poured into 1 N sodium hydroxide, extracted with ether, the eluate washed with 1 N sodium hydroxide and with water, and the so-obtained ether phase dried over sodium sulfate and evaporated.
• the residue was then twice decanted each time with 0.5 liter of low boiling petroleum ether.
• the petroleum ether insoluble part, a viscous yellow oil consisted of crude 1 methyl 2 (3-nitro-benzyl)-l,Z-dibenzoyl-hydrazine. Without further purification, this crude product was dissolved in 200 ml. of acetate acid and the resulting solution, after addition of 200 ml. of concentrated hydrochloric acid, boiled for 2 hours under a nitrogen atmosphere. The concentrate obtained by evaporation under reduced pressure was then partitioned between water and ether.
• Example 6 First, 2.05 g. of sodium and then 28 g. of 1-methyl-l,2- dicarbobenzoxy-hydrazine were dissolved in 150 ml. of absolute ethanol, and the solution was evaporated to dryness under reduced pressure. The residue was dissolved in 100 ml. of dimethylformamide, and to this solution were added at one time with stirring 20.5 g. of 4-(bromomethyl)-benzamide. The reaction was exothermic and the temperature of the reaction mixture rose to about 60. The reaction mixture was stirred for 2 hours, then poured into 500 ml. of water and extracted three times with ether/ methylene chloride (3:1).
• Example 7 A solution of 2.3 g. of sodium in 150 ml. of absolute ethanol was treated with 31.4 g. of l-methyl-l,2-dicarbobenzoxyhydrazine and then with a solution of 18.3 g. of 3-acetamidobenzyl chloride in 50 ml. of absolute ethanol. The mixture was then heated to a boil with stirring for 2 /2 hours, cooled and evaporated in vacuo. The oily residue was partitioned between methylene chloride and water, and worked up as usual. The crude l-methyl-2-(3- acetamido benzyl) 1,2 dicarbobenzoxyhydrazine was hydrogenated in 200 ml. of methanol with palladium carbon as the catalyst.
• the solvent was evaporated oif, the residue taken up in 50 ml. of absolute ethanol and treated with a solution of 12.6 g. of oxalic acid and alcohol.
• the first colloidal precipitate was rendered solid by trituration with methanol and then recrystallized from methanol/ether, yielding 1 methyl 2 (3 acetamido benzyl) hydrazine oxalate, melting at 175 (dec.).
• Example 8 A mixture of 12 g. of methylhydrazine, 37.3 g. of 4-dimethylarnino-benzaldehyde, 200 ml. of ethanol and 0.5 ml. of acetic acid was heated under a nitrogen atmosphere to the boiling point for 5 minutes. After cooling to 20 and without isolation of the intermediate hydrazone, the reaction mixture was hydrogenated under normal conditions in the presence of 2 g. of platinum in the form of platinum oxide (Adams catalyst). The hydrogenation was interrupted after the uptake of 6.5 liters of hydrogen, the catalyst filtered off, rinsed with 20 ml. of ethanol, and the purified filtrate along with the rinse ethanol concentrated at 40 (bath temperature)/ 12 mm. Hg. The oily brown colored residue was purified by fractional distillation under a nitrogen atmosphere, yielding l-methyl-2-(4-dimethy-lamino-benzyD-hydrazine, which boiled at 131/0.3 mm.
• Example 9 A mixture of 37.6 g. of 3-nitro-benzaldehyde, 100 ml. of methylalcohol, 50 ml. of aqueous methylhydrazine solution (obtained from 26 g. of methylhydr-azine) and 1 ml. of acetic acid were heated to boil for 10 minutes. The deep red colored solution was cooled to 4 and permitted to stand overnight. The crystals that separated were filtered 01f, washed with aqueous ethanol and dried in vacuo. The filtrate and wash liquid were concentrated under reduced pressure to about V2 their volume. Upon cooling, further substance crystallized out. The crude dried l-methyl 2 (3 nitro benzylidene) hydrazine was twice recrystallized from ether/petroleum ether and melted at 66.
• Example 10 14.92 g. of 4-dimethylamino-benzaldehyde in 100 ml. of ethyl alcohol were added to an aqueous acetic acid solution of l-methyl-l-acetyl-hydrazine. The reaction mixture was then heated to a boil for 5 minutes, the clear red solution cooled downand the separated crystals of 1- methyl-2-(4 dimethylaminobenzylidene) 1 acetyl-hydrazine filtered off. This intermediate was twice recrystallized from methanol and melted at 127-129".
• Example 11 First 0.62 g. of sodium and then 8.8 g. of 1-rnethyl-1,2- dicarbobenzoxy-hydrazine were dissolved in 50 ml. of absolute ethanol and the solution evaporated to dryness under reduced pressure. The residue was dissolved in 50 ml. of dimethylformamide and treated with a solution of 9.8 g. of N-(N-carbobenzoxy-DL-a-alanyl) 4 chloromethyl-aniline in ml. of dimethylformamide. After 10 minutes, the reaction mixture reacted neutral. It was then poured in water and, extracted with methylene chloride, the extract was washed with water and dried with sodium sulfate.
• the methylene chloride was distilled off in vacuo, the residual oil dissolved in 300 ml. of methanol and hydrogenated in the presence of palladium-carbon until the carbobenzoxy groups were completely split off.
• the catalyst was filtered off, the filtrate was adjusted to a pH of 5 with alcoholic hydrochloric acid, concentrated to a small volume in vacuo and treated with ethyl acetate.
• the precipitated hydrochloride of l-methyl- 2 [4 (DL-a-alanyl-amino)-benzyl]-hydrazine was an amorphous hygroscopic powder, which decomposed a 95100.
• Example 12 31.4 g. of 1 methyl 1,2 dicarbobenzoxy-hydrazine were added portionwise, with stirring at -30, to a suspension of 2.4 g. of sodium hydride in 100 ml. of dimethylformamide. The reaction mixture was then stirred until the hydrogen evolution had terminated and all the material had gone into solution. A solution of 23 g. of 4-phenylazo-benzyl chloride in 100 ml. of dimethylformamide was then added dropwise thereto, with stirring, in the course of minutes. After the addition was terminated, the mixture was stirred for a further 2 hours at 80, then cooled and the solvents evaporated off in vacuo as far as possible. The deep red oily residue was partitioned between 300 ml.
• Example 13 A solution of 8.9 g. of 5-methyl-3-isoxazole-carbonyl chloride in 30 m1. of absolute benzene was added dropwise, with stirring, so that the temperature did not rise over 40, to a solution of 20 g. of 1-methyl-2-(4-aminobenzyl)-1,2-dicarbobenzoxy-hydrazine in 30 ml. of absolute pyridine. After the addition, the reaction mixture was stirred for 16 hours at room temperature and then treated with 200 ml. of water. The aqueous phase was twice extracted, each time with 300 ml. of benzene. The benzene extracts were extracted 3 times, in all with 400 ml.
• Example l4 15 g. of 4-[(Z-methyl-l,2-dicarbobenzoxy-hydrazino) methyl]-benzoic acid were boiled with an excess of thionyl chloride for 1 hour under reflux. The unconverted thionyl chloride was distilled off in vacuo, the residue twice dissolved each time in ml. of absolute benzene and then concentrated in vacuo. The so-obtained 4-[(2- methyl 1,2 dicarbobenzoxy-hydrazino)methyl]-benzoyl chloride, a viscous light yellow oil, was dissolved in 50 ml. of absolute benzene and with stirring mixed with a solution of 4.45 g. of isopropylamine in 100 ml.
• reaction mixture was boiled for a further 20 hours, then concentrated in vacuo and the product, 4-methyl-benzoic acid methyl ester, isolated by conventional means. It could be purified by distillation, and the purified product boiled at 9l/9 mm. Hg, M.P. 32.
• Example 15 16.5 g. of 4-[(Z-methyl-1,2-dicarbobenzoXy-hydrazino)- methyl]-benzoyl chloride were added to ml. of absolute benzene and treated with 3.1 g. of cyclopropylamine hydrochloride. 7.5 g. of triethylamine and 50 ml. of benzene were then dropped into the reaction mixture at 20-30 with stirring. The reaction mixture was worked up as in Example 14, yielding 4-[(Z-methyl-1,2-dicarbobenzoxyhydrazino)-methyl]-benzoic acid cyclopropylamide, the carbobenzoxy groups of which were then removed by treatment with hydrogen bromide/ glacial acetic acid. The product, 4-[(Z-methyl-hydrazino)-methyl]-benzoic acid cyclopropylamide hydrobromide, melted at 180-182.
• Example 16 Reaction of 16.5 g. of 4-[ (Z-methyl-1,2-dicarbobenzoxyhydrazino)-methyl]benzoyl chloride with morpholine according to the process of Example 14 above yielded the reaction product as a viscous yellow oil.
• the carbobenzoxy groups were split 01f by hydrogenolysis as follows:
• Example 17 14.1 g. of 4-[(Z-methyl-1,2-dicarbobenzoxy-hydrazino)- methyl] -benzoyl chloride in 20 ml. of benzene were added to a mixture of 13.2 g. of glycine benzylester tosylate and 100 ml. of absolute pyridine. After the mixture stood for one hour at room temperature, it was worked up in the usual manner and the crude condensation product was hydrogenolysed in methanol with palladium-carbon as the catalyst. The so-obtained N-[4-[(2-methyl-hydrazino)- methyl]-benzoy1]-glycine, after recrystallization from water/alcohol, melted at 209-2l0 (dec.).
• the same product was obtained by a reaction of 4-[(2- methyl-1,2-dicarbobenzoxy-hydrazino)-methyl] benzoic acid and glycine benzylester tosylate in methylene chloride in the presence of triethylamine and dicyclohexyl-carbodiimide. After removal of the formed dicyclohexylurea by filtration under suction, the methylene chloride solution was washed with dilute hydrochloric acid and sodium bicarbonate solution, then concentrated. The product was then hydrogenolysed as described above.
• Example 18 17 g. of L-glutamine 4-nitrobenzyl ester hydrobromide in 120 ml. of absolute pyridine were treated with a solution of 22 g. of 4-[(Z-methyl-1,Z-dicarbobenzoxy-hydrazino)-methyl]-benzoyl chloride in 50 ml. of benzene, and then worked up as in Example 17.
• Example 19 5.75 g. of sodium and then 79 g. of 1-methyl-1,2-dicarbobenzoxy-hydrazine were dissolved in 250 ml. of absolute alcohol. The solution was evaporated to dryness in vacuo at 40 and the residue dissolved in 150 ml. of dimethylformamide. Over ten minutes, 46 g. of 4-chloromethyl-thioanisole were added to the solution, the temperature of the reaction mixture rising to 60. The reaction mixture was then stirred for two hours at room temperature, poured into 1.5 liters of water and extracted with methylene chloride/ ether. The extracts were washed several times with water, dried with sodium sulfate and concentrated in vacuo. The oily residue was dissolved in 400 ml.
• Example 20* g. of 4-[(2-methyl-1,2-dicarbobenzoxy-hydrazino)- methyl[-benzoy1 chloride were dissolved in a mixture of 50 ml. of benzene and 10 ml. of pyridine. While stirring, this solution was treated with 8 g. of l-methyl-2-(4-aminobenzyl)-1,2-dicarbobenzoxy-hydrazine in 30 ml. of henzene. After standing for one hour at room temperature, the reaction mixture was poured into water and extracted with methylene chloride. The methylene chloride extract was washed with sodium bicarbonate solution, dried with sodium sulfate and then concentrated.
• Example 21 By reaction of 23.4 g. of 4-[(2-methyl-1,2-dicarbobenzoxy-hydrazino)-methyl]-benzoyl chloride with 4.85 g. of furfurylamine in a mixture of 8 ml. pyridine and 50 ml. of benzene according to the procedure of Example above, followed by hydrogenolysis of the condensation product with palladium-carbon in methanol, there was obtained 4-[ (2-rnethyl-hydrazino) -n1ethyll benzoic acid 16 furfurylamide, the oxalate of which melted at 170-171 (dec.).
• Example 22 23.4 g. of 4- (2-methyl-1,2-dicarbobenzoxy-hydrazino) methyl]-benzoyl chloride were dissolved in 60 ml. of benzene and, with stirring and cooling, added dropwise to a solution of 13.4 g. of Z-diethylamino-ethylamine in 20 ml. of benzene. The mixture was permitted to stand overnight and then partitioned between a dilute solution of sodium hydroxide and ether. The ether phase was Washed thoroughly neutral with Water and then extracted with A N hydrochloric acid. The hydrogen chloride extract was rendered strongly alkaline with sodium hydroxide, and then again extracted with ether.
• the ether solution was washed neutral with water, dried with sodium sulfate, and evaporated.
• the residual yellow oil was dissolved in 75 m1. of a 33% solution of hydrogen bromide in glacial acetic acid, and the resulting mixture permitted to stand for three hours at room temperature. It was then treated with ether, whereupon a hygroscopic salt separated out. This was separated and then dissolved in the minimum amount of water.
• the solution was then saturated with potassium carbonate and extracted with methylene chloride. The methylene chloride extracts were dried with potassium carbonate and concentrated.
• Example 23 9 g. of ethanolarnine were dissolved in a solution of 18.2 g. of sodium carbonate in 200 m1. of water. Over two hours, a solution of 65 g. of 4-[(2-methyl-l,2-dicarbobenzoxy-hydrazino)-methyl] -benzoyl chloride in ml. of ether was then added thereto dropwise with vigorous stirring at 0-5 The reaction mixture was then stirred overnight at 0-5. It was then extracted with a mixture of methylene chloride and ether, and the extract washed with water, 1 N hydrochloric acid, potassium bicarbonate solution and water, dried with sodium sulfate, and evaporated.
• Example 24 13.5 g. of diethanolamine were dissolved in a solution of 14.5 g. of sodium carbonate in 160 ml. of water. In the course of 2 hours, a solution of 52 g. of 4-[(2- methyl 1,2 dicarbobenzoxy-hydrazino)-methyl]-benzoyl chloride in 150 ml. of ether was added thereto dropwise with vigorous stirring at O-5. The mixture was then stirred overnight at 0-5. It was extracted with ethyl acetate and the ethyl acetate solution washed with sodium bicarbonate solution and sodium chloride solution, dried with sodium sulfate and evaporated. The residual viscous yellow oil was dissolved in 500 ml.
• Example 25 g. of 1-methyl-2-(4-aminobenzyl)-l,2-dicarbobenzoxy-hydrazine were dissolved in ml. of pyridine, and, with stirring and cooling, 6.4 g. of pivaloyl chloride in 10 ml. of benzene were added thereto dropwise.
• the reaction mixture was then permitted to stand Overnight at room temperature, poured into 400 ml. of water, taken up in ether, and the ether solution washed with water, 3 N hydrochloric acid, potassium bicarbonate solution and Water, dried with sodium sulfate, and evaporated.
• the residual yellow oil was dissolved in 70 ml.
• Example 26 20 g. of 1-methyl-2-(4-amino-benzyl)-1,2-dicarbobenzoxy-hydrazine were dissolved in 100 ml. of 85% acetic acid. With stirring at 30-35, a solution of -6 g. of sodium cyanate in ml. of water was then added dropwise to the mixture. The reaction mixture was then stirred for 1 /2 hours at poured into 850 ml. of water, taken up in ether and washed with water, 3 N hydrogen chloride, potassium bicarbonate solution and water. After drying with sodium sulfate, the ether was distilled off and the residual viscous oil dissolved in 70 ml. of a 33% solution of hydrogen bromide in glacial acetic acid.
• Example 27 18.9 g. of l-methyl-2-(4-amino-benzyl)-1,2-dicarbobenzoxy hydrazine were dissolved in 50 ml. of ethanol, treated with one equivalent of ethanolic hydrochloric acid and 2.7 g. of cyauamide, and then boiled under reflux for 18 hours. The reaction mixture was then evaporated in vacuo, the residue dissolved in water, rendered alkaline with sodium hydroxide, and extracted with ether/methylene chloride. The extract was washed with water, dried with sodium sulfate and evaporated. The residual yellow oil was shaken overnight at room temperature with ml. of a 33% solution of hydrogen bromide in glacial acetic acid.
• Example 28 30 g. of 1-methyl-2-(4-amino-benzyl)-1,2-dicarbobenzoxy-hydrazine were reacted with 9 g. of methylsulfonyl chloride according to the procedure described in Example 25. After the reaction mixture was poured into water, it was extracted with a mixture of ether and methylene chloride.. It was then washed with water, 3 N hydrochloric acid, potassium bicarbonate solution and water, dried with sodium sulfate and evaporated. The so-obtained residual yellow oil was dissolved in ml. of 33% solution of hydrogen bromide in glacial acetic acid, and permitted to stand for 3 hours at room temperature. The precipitated crystals were isolated and purified as previously described, yielding l-methyl-Z-(4-methylsulfonylamino-benzyl)-hydrazine hydrobromide melting at 177-178.
• Example 29 106.5 g. of 4-[(2-methyl-1,Z-dicarbobenzoxy-hydrazino)-methyl] -benzoyl chloride were dissolved in 400 ml. of diethyleneglycol dimethylether, and, with stirring in the course of 1 /2 hours at -75 to -68, treated with a suspension of 70 g. of tri-tert.-butoxy-lithium-aluminum-hydride in 400 ml. of diethyleneglycol dimethylether. The temperature of reaction mixture was then allowed to rise to 0 in the course of 1 hour and then the mixture was treated with 60 ml. of water and 25.5 ml. of 3 N sodium hydroxide.
• reaction mixture was poured into a large amount of water, acidified with hydrochloric acid and the crude aldehyde taken up in ether.
• the ether solution was washed three times with 3 N hydrochloric acid, two times with water, four times with sodium hydroxide solution and a further three times with water, dried with sodium sulfate and concentrated, yielding crude 4[(2-methyl-1,Z-dicarbobenzoxy-hydrazino)- methyl] -benzaldehyde.
• this product was dissolved in about 40 ml. of glacial acetic acid, and to this solution were added 280 ml.
• Example 31 23.8 g. of 4-[(2-methyl-1,2-dicarbobenzoxy-hydrazino)-methyl] -benzoic acid (Z-hydroxy-ethyl) -amide (obtained according to Example 23) were dissolved in 240 ml. of methanol and shaken in a hydrogen atmosphere together with 5 g. of palladium-carbon until the carbobenzoxy groups were hydrogenerated off. The catalyst was then filtered 01f and the filtrates were concentrated. The residue was dissolved in 20 ml. of ethanol and treated with 1 1 9 equivalent of alcoholic hydrochloric acid.
• Example 32 87.5 g. of 4-[(2-methyl-hydrazino)-methyl]-benzoic acid isopropylamide hydrobromide (obtained according to Example 14) were dissolved in 550 ml. of water. To this solution, there were added 1000 ml. of methylene chloride and, while cooling with ice and stirring under nitrogen atomosphere, 1200 g. of potassium carbonate portionwise. The methylene chloride layer was separated and the aqueous slurry extracted three times with 500 ml. of methylene chloride in a nitrogen atmosphere. The united methylene chloride extracts were concentrated in vacuo. The residue was dissolved under nitrogen in 100 ml. of methanol and treated, while cooling with ice, with ml.
• Example 33 A solution of 15.5 g. of 4-[(2-methyl-1,2-dicarbobenzoxy-hydrazino)-methyl]-benzoyl-chloride in ml. of methylene chloride was poured, while stirring, to a solution of 2-(N-carbobenzoxy-methylamino)-ethylamine in 50 ml. of methylene chloride and 3.5 g. triethylamine. The mixture was stirred for 3 hours at room temperature and for 30 minutes at 40, then poured onto water. The methylene chloride layer was separated and washed with 1 N hydrochloric acid and with water. The methylene chloride solution was dried and concentrated and the residue dissolved in ml.
• Example 34 7.4 g. of methyl urea, 46.7 g. of 4-[(2-n1ethyl-l,2- dicarbobenzoxy hydrazino) methyl]-benzoyl chloride, of 8 g. of pyridine and 200 ml. of benzene were mixed and refluxed for 8 hours. After cooling down, the mixture was poured ontowater and extracted with an ether/ methylene chloride mixture. The extract was washed with water, with l N hydrochloric acid and again with water dried over sodium sulfate and freed of the solvent by distillation. The residue crystallized upon triturating with methanol.
• Example 36 21.5 g. of 4[(Z-methyl-1,2-dicarbobenzoxy-hydrazino)- methyl]-benzonitrile were dissolved in 70 ml. of a 33% solution of hydrogen bromide in glacial acetic acid, and allowed to stand for 20 hours at room temperature. The crystallized product was filtered oif, washed with ether and recrystallized from alcohol, yielding 4-[(2-methylhydrazino) methyl] benzamide hydrochloride melting at 173-175".
• Example 37 15.8 g. of 4-[Z-methyl-1,Z-dicarbobenzoxy-hydrazino)- methyl]-benzoyl-chloride were dissolved in 50 ml. of methylene chloride and, while stirring, added dropwise to a solution of 6.2 g. of 2-amino-1-butanol in 50 ml. of methylene chloride. Stirring was continued for 2 more hours at room temperature and 30 minutes at 40, whereupon 50 ml. of water were added to the solution, which was then worked up according to Example 14. The yellowish glassy materialobtained was dissolved in 200 ml. of methanol, shaken with 2 g.
• Example 38 propanol and 3.6 g. of anhydrous sodium carbonate in 50 ml. of water. The solution was stirred overnight at the mixture diluted with 100 ml. of water and extracted three times with 100 ml. of methylene chloride each time. The united methylene chloride extracts were freed of the solvent in vacuo and the residue dissolved in 200 ml. of methanol, whereupon it was hydrogenated in the presence of 2 g. of palladium carbon. The colorless glacial material was transformed according to Example 37 into its oxalic acid salt.
• Example 39 The condensation product obtained in Example 38 from 4-[(2-methyl 1,2 dicarbobenzoxy-hydrazino)- methylJ-benzoly-chloride and 2 amino-2-methyl-1-propanol gave, upon treatment with hydrogen bromide in glacial acetic acid and subsequent precipitation with ether, an amorphous material that was dissolved in 50 ml. of water. To this solution were added 300 ml. of methylene chloride and, while cooling with ice under nitrogen, 150 g. of anhydrous potassium carbonate. The solution was well stirred, the organic phase decanted and the aqueous phase extracted three times with 300 ml. of methylene chloride each time.
• dimethyl2-acetoxy-ethyl)-amide oxalate formed color-' less crystals melting at 116-126 (dec.) after 2 recrystallizations from ethanol.
• Example 40 15.8 g. of 4-[(2-methyl-1,2-dicarbobenzoxy-hydrazino)- methylJ-benzoyl chloride were dissolved in 50 ml. of methylene chloride. This solution was added, while stirring, dropwise to a suspension of 12.6 g. of Z-hydroxy- 3,3,3-trichloro-propylamine in 150 ml. of methylene chloride. Stirring was continued for 2 hours at room temperature and minutes at whereupon ml. of water were added thereto. The product was worked 22 up according to Example 14 and treated with hydrogen bromide in glacial acetic acid.
• Example 41 6.4 g. of phosphorous pentachloride were suspended in 100 ml. of dry benzene. To this suspension was added, while stirring, a solution of 4-[(2-methyl-1,2-dicarbobenzoxy-hydrazino)-methyl]-benzoic acid isopropylamide in 50 ml. of dry benzene. After 30 minutes, the solution became yellow and was concentrated in vacuo at 60. The residue was treated with 1.8 g. of isopropylamine in 50 ml. of dry benzene and the mixture was heated to 60 for 2 hours. After evaporating oil the solvent, there was obtained a yellow glacial material that was taken up in ml.
• Example 42 55.5 g. of 1-methyl-2-(4-amino-benzyl)-1,2-dicarbobenzoxy-hydrazine were dissolved in 250 ml. of absolute benzene. To this solution were added while stirring, 14.5 g. of N-butyl-isocyanate and the reaction mixture heated for 5 hours at 55, whereupon the benzene was distilled ofl in vacuo. The residue was dissolved in ether and the ether solution washed with 3 N hydrochloric acid and with water, dried with sodium sulfate and concentrated. The viscous oily residue was dissolved in 200 ml. of a 33% solution of hydrogen bromide in glacial acetic acid, whereupon crystallization soon began.
• Example 43 42 g. of 4-[(2-methyl 1,2 dicarbobenzoxy hydrazino)-methyl]-benzoic acid azide, which had been prepared in usual manner from 4-[(2-methyl-1,2-dicarbobenzoxy-hydrazino)-methyl] -benzoyl chloride and sodium azide, Were heated in 170 ml. of toluene to until the evolution of nitrogen had subsided. The residue obtained after distilling off the toluene in vacuo was recrystallized from dibutyl ether yielding l-methyl-2-(4-isocyanatobenzyl)-1,2-dicarbobenzoxy-hydrazine of melting point 55-57". This product was dissolved in 100 ml.
• n is a whole integer from 0 to 1
• R and R are each selected from the group consisting of hydrogen, phenyl, benzyl, lower alkanoyl, and lower alkoxy.
• a compound as in claim 1 which is of the formula OHzNHNHCHs CHzNHNHCHa OHzNHNHCHa 3.
• a compound as in claim 2 which is 1,2-bis-[(2- methyl-hydrazino)-methyl] -benzene.
• a compound as in claim 2 which is 1,4bis-[(2- methyl-hydrazino)-methy1]-benzene.
• a compound as in claim 1 which is of the formula 6.
• a compound as in claim 5 which is 3,3'-bis[(2- methyl-hydrazino -methyl] -bipheny1.

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